"Dr David Bell and I will attempt to replicate the Rituximab study. David is enthusiastic in doing this as he retired from active practice and will come to New York to work with us in the new ME/CFS center."

Its been very long since I dont read or write here. I have experienced a HUGE improvement with GcMAF, that has allowed me to enroll at the medicine school, and I am devoting all my energy to my new life of student. I estimate I am at my 60%, but I feel a bit better after every weekly injection, so I think I still have a good margin of improvement ahead of me time will tell!

The thing is that I am just trying to catch up with this new study of Rituximab on CFS, and I wanted to thank you for having, as always, given a step back to see the whole elephant, and as a result, having given in a so scientifically way a convincing explanation for the Rituximab study results, again, matching them with your GD-MCB theory.

As Sushi and others have asked you, Id really like you to try to give a similar possible explanation for the so good results GcMAF is showing Unlike Rituximab, this is a non-toxic natural protein our immune system work with, and its results seem to be impressive for many of us, and seem to be permanent so far

I cannot find an explanation for the so good results of GcMAF if we think of CFS as an autoimmune disease, unless some exogenous or even endogenous retroviruses are actually the real cause behind the autoimmunity, as some researchers have speculated May I ask whats your take on this?

It's great to hear from you, and I'm so glad to hear how well you are doing!

As you know, I offer a lot of hypotheses. Time will tell whether they are actually valid.

O.K., here's my hypothesis for GcMAF in ME/CFS, in the light of the GD-MCB hypothesis for the pathophysiology of this disorder:

A person who has ME/CFS has a dysfunctional immune system. I believe that this results from glutathione depletion and the vicious circle mechanism it causes (which includes a functional deficiency in B12, a partial block in the methylation cycle, and draining of folate from the cells).

This dysfunction includes low natural killer cell and low cytotoxic T-cell (CD8) activity as a result of inability of these cells to produce enough perforin and granzymes, which I have suggested results from glutathione depletion in these cells.

Because of this dysfunction, the immune system is not able to effectively deal with viral infections.

Another effect of the glutathione depletion is that the normally latent herpes family viruses are allowed to reactivate, because glycoprotein B is able to form disulfide bonds.

So now the viruses are reactivated, and the immune system's normally most effective antiviral responses are not functioning well.

The depletion of glutathione also causes a shift to the Th2 immune response, and this allows intracellular bacteria to go unchallenged, also.

The immune system is left with trying to fight these infections with antibodies and also with the RNase-L system, which is supposed to be a temporary response, but because the cell-mediated immune response does not rise up to take over the fight, it remains activated.

This constitutes a guerrilla war, with neither side winning. Some of the cytokines that are produced are proinflammatory, and this produces inflammation and oxidative stress, placing an ongoing demand on glutathione, thus helping to preserve the vicious circle mechanism that is at the core of the pathogenesis of ME/CFS.

O.K., that's the status of the immune system in the person who has ME/CFS.

Now, let's consider the GC protein:

The liver normally produces GC protein (also known as vitamin D binding protein) and exports it to the blood.

If an activated B cell and a T cell act on this protein with their respective membrane-mounted enzymes, they convert it to GcMAF

GcMAF activates the macrophages.

The activated macrophages express a variety of receptors that recognize virions, and they thus engulf and kill any of them they find outside of cells.

The activated macrophages also kill intracellular bacteria that are in vesicles inside them.

Certain viruses produce nagalase, which prevents the normal conversion of the Gc protein to
GcMAF, thus preventing the macrophages from activating.

Treating a person with exogenously prepared GcMAF overcomes the nagalase inhibition, and activates the macrophages, so that they can kill viruses and intracellular bacteria.

When these pathogens have been killed, the immune system stops the production of proinflammatory cytokines, and the inflammation decreases.

This decreases the oxidative stress, and this takes demand off glutathione, which allows it to rise.

The more glutathione rises, the more the symptoms decrease.

If glutathione is able to come up far enough, and a high enough ratio of reduced to oxidized glutathione can be achieved, there is hope that the vicious circle mechanism can be broken, and the person can recover.

The Rituximab treatment was apparently able to achieve this in some of the patients treated. In those cases, I suggest that knocking out the B cells caused enough of a decrease in the inflammation that glutathione was able to recover enough to correct the vicious circle mechanism and the immune dysfunction, so that when the B cell population came back up, there was no longer a Th2 shift. Perhaps this also knocked out viruses such as EBV that reside inside B cells, as Nancy Klimas has suggested.

"Dr David Bell and I will attempt to replicate the Rituximab study. David is enthusiastic in doing this as he retired from active practice and will come to New York to work with us in the new ME/CFS center."

This is a good point and one that is applicable to all trials using placebos with double-blinding in which the active drug has distinctive side effects - there are cues that patients might be able to use to determine that they're on the active medication even with the blinding. Researchers are aware of it and it's hard to get around. Like a lot of these things, it's less likely as the explanation for the result of the trial if the difference between active drug and placebo groups is big. I think that in the case of this trial, the late-arriving improvement is also an argument against patients simply getting a bigger placebo/perceived improvement boost from Rituximab - I'd expect those effects to kick in pretty quickly.

Personally, I've always been surprised that researchers are not required as standard in every trial to ask patients whether they think they have been administered the active drug or placebo. At least they'd then have a measure of patients' ability to tell which condition they're in, despite the attempts at blinding.

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I see your point Sasha. As to whether or not they could feel it, I find the pretty similar side effect profile in placebo and medicine group really encouraging. And, the drug was given with a high dose corisol injection (both in placebo and the medicine group). That will stir things around for many, if not most PWME, and probably lead to a larger proportion assuming they got the drug. Rituximab is in most cases not particularly noticeable during infusion, but the corisol is often highly noticeble at those doses.

I agree with your last point. It's good to have that information for later, when the unblinding occurs.

Thanks Snow Leopard and all you Scientists. An uncanny link in my family here. I went down with full blown ME - my brother (a Doc in the States) has been diagnosed PML when taking no drugs whatsoever. Whilst I improve unfortunately he does not. (Old Dad died of Prostrate Cancer - so something much interlinked I feel going on).

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I am sorry to hear that Enid. You could check the other Rituximab thread, as some novel treatment methods for PML are menioned there. I've heard it's lethal in most cases, so I guess a "leave no stone unturned" is the best approach.

I have to admit that I always feared the rituximab findings would be used to re-cast ME as an auto-immune disease and distract from a retroviral hypothesis.

The type of B cells that are killed by rituximab (CD20) are the same ones that Judy Mikovits said contained the retrovirus.

In fact I remember her coming up to talk directly after Dr Mella and as she came to the stage she said that she was not surprised by their findings as the virus was in the CD20 B cells.

She praised their study. (That bit is not on the DVD)

At the conference the norwegians said they had failed to find XMRV but they also said they could not identify the expected autoantibodies either.

(I will now read the paper to see if they have found them yet.)

In the published paper the authors are open to a viral etiology in the form of a B-lymphotropic virus.

However they prefer an autoimmune hypothesis.

So the cause is as yet unknown.

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I think you're right. I also still think it's XMRV. BUT; it doesn't matter as long as the drug works and we get well. There will be many of those who get well and of others that have taken up the research on XMRV that will continue the research on it and keep pushing for it. Personallly I think that NIH is so scared of people knowing there's another retrovirus out there that they want to keep this shut. Another "new HIV"-stir up would create panic amongst people and that in combination with the costs of it all is exactly what they don't want. Question is though, how mush do they lose in disability pay-outs compared to what it would cost them to treat the patients who then could work and pay incometaxes. But..it's all relative, I guess...

Whatjustifications do you have to be absolutely convinced about that? I partly ask this question because I don't believe there are justifications to make that claim. Afterall, if it was that clear-cut the pathophysiology of ME/CFS would be well-known and treatment options would be available or in progress.

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I wrote a long reply to this, but then clicked off the page by accident. Too tired to type it out again. Here is a much shorter version:

1. Most people get EBV. I had mono very bad as do many ME/CFS sufferers. Many have or had it without knowing.
2. Stress (mental or physical) can cause reactivation of EBV. This includes high level exercise, like swimming alot.
3. Ritoximab knocks out the B cells, where EBV is known to hide. BUt some people relapse. Maybe EBV is in the bone marrow.
4. Lipkin and Klimas clearly think an infection is the cause, and have mentioned EBV as a top suspect. They, along with Montoya and Lerner are the best in the field, IMO.
5. EBV is a complex virus which we dont know everything about, particularly its knock on affect on the immune system. So its not a surprise that we havent figured it all out yet. Particularly when you consider that an illness like ours picks up other 'sick' people with other stuff thats hard to identify, and benefit frauds, because its easy to claim the illness when you havent got it.
6. Some people like me have a strong immune system, overactive, meaning they dont catch colds etc. But some have the opposite, and some start with the former but their immune system goes downhill. With a weakened immune system your going to catch everthing, which perhaps explains coinfections and infestations which seem common with PWME, and especially those who have had it longest. I would suggest looking at early ME/CFS sufferers, rather than those who have had it a while, as they may have other stuff that may mislead research.
7. EBV may not be the only cause. Perhaps other viruses, like those mentioned, cause the same affect on B cells. As it goes i am skeptical about some blood tests, they arent always clear cut. They represent our best methods of finding something. Who is to say you havent got EBV, just because an antibody or PCR test came back negative?

I am not medically trained. But i am a decent analyst who is used to finding the root cause of problems, so to me, EBV looks by far the most likely cause.

Active EBV is definitely found in quite a few PWMEs. It does reside in its latent state in immortalized B cells. Rituximab does knock out B cells.

Based on the work of Palamara et al. at the University of Rome, a healthy ratio of reduced to oxidized glutathione is able to prevent proliferation of herpex simplex type 1 by preventing the formation of disulfide bonds in glycoprotein B. The other herpes family viruses, including EBV, also have glycoprotein B. I conclude from this that a healthy ratio of reduced to oxidized glutathione also suppresses proliferation of EBV.

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Rich, i dont know or understand much about this yet, but i am very interested. Can you point me to some posts about this, or PM me with more info?

Thanks redo -your post 433 - my brother is in the States at a major University Hospital (he's a Neurologist) so in the best hands possible. I see the JC virus is one of so many latent and treatable now. He is indeed improving and I think our common problem is of the immune system (possible genetic predisposition). The trigger virus that initially disrupts immune function allowing "latents" to appear would be quite a find.

If I'm not mistaken Rich,you mention viral infection as one of the possible stressors that starts the vicious cycle. Is it not possible a virus that is able to get into our cells for some reason starts the process ? I mentioned a book I received from the library on glutatione. They showed that the 3 viruses they studied (HSV, influenza and HIV) all caused profound decreases in cellular glutathione.

In my case, I have enterovirus and it does make sense as I grew up spending a lot of time at a cottage using well water and my aunt has the same symptoms. I was not breastfed which would have negatively affected my immune system. Maybe a big enough dose of the virus would have circumvented the ability of my immune system to contain it and let it infect my cells and then reduce glutathione.

It's great to hear from you, and I'm so glad to hear how well you are doing!

As you know, I offer a lot of hypotheses. Time will tell whether they are actually valid.

O.K., here's my hypothesis for GcMAF in ME/CFS, in the light of the GD-MCB hypothesis for the pathophysiology of this disorder:

A person who has ME/CFS has a dysfunctional immune system. I believe that this results from glutathione depletion and the vicious circle mechanism it causes (which includes a functional deficiency in B12, a partial block in the methylation cycle, and draining of folate from the cells).

This dysfunction includes low natural killer cell and low cytotoxic T-cell (CD8) activity as a result of inability of these cells to produce enough perforin and granzymes, which I have suggested results from glutathione depletion in these cells.

Because of this dysfunction, the immune system is not able to effectively deal with viral infections.

Another effect of the glutathione depletion is that the normally latent herpes family viruses are allowed to reactivate, because glycoprotein B is able to form disulfide bonds.

So now the viruses are reactivated, and the immune system's normally most effective antiviral responses are not functioning well.

The depletion of glutathione also causes a shift to the Th2 immune response, and this allows intracellular bacteria to go unchallenged, also.

The immune system is left with trying to fight these infections with antibodies and also with the RNase-L system, which is supposed to be a temporary response, but because the cell-mediated immune response does not rise up to take over the fight, it remains activated.

This constitutes a guerrilla war, with neither side winning. Some of the cytokines that are produced are proinflammatory, and this produces inflammation and oxidative stress, placing an ongoing demand on glutathione, thus helping to preserve the vicious circle mechanism that is at the core of the pathogenesis of ME/CFS.

O.K., that's the status of the immune system in the person who has ME/CFS.

Now, let's consider the GC protein:

The liver normally produces GC protein (also known as vitamin D binding protein) and exports it to the blood.

If an activated B cell and a T cell act on this protein with their respective membrane-mounted enzymes, they convert it to GcMAF

GcMAF activates the macrophages.

The activated macrophages express a variety of receptors that recognize virions, and they thus engulf and kill any of them they find outside of cells.

The activated macrophages also kill intracellular bacteria that are in vesicles inside them.

Certain viruses produce nagalase, which prevents the normal conversion of the Gc protein to
GcMAF, thus preventing the macrophages from activating.

Treating a person with exogenously prepared GcMAF overcomes the nagalase inhibition, and activates the macrophages, so that they can kill viruses and intracellular bacteria.

When these pathogens have been killed, the immune system stops the production of proinflammatory cytokines, and the inflammation decreases.

This decreases the oxidative stress, and this takes demand off glutathione, which allows it to rise.

The more glutathione rises, the more the symptoms decrease.

If glutathione is able to come up far enough, and a high enough ratio of reduced to oxidized glutathione can be achieved, there is hope that the vicious circle mechanism can be broken, and the person can recover.

The Rituximab treatment was apparently able to achieve this in some of the patients treated. In those cases, I suggest that knocking out the B cells caused enough of a decrease in the inflammation that glutathione was able to recover enough to correct the vicious circle mechanism and the immune dysfunction, so that when the B cell population came back up, there was no longer a Th2 shift. Perhaps this also knocked out viruses such as EBV that reside inside B cells, as Nancy Klimas has suggested.

Is it not possible a virus that is able to get into our cells for some reason starts the process ? I mentioned a book I received from the library on glutatione. They showed that the 3 viruses they studied (HSV, influenza and HIV) all caused profound decreases in cellular glutathione.

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What's the name of the book? I'd like to buy it if I can

I noticed while looking for studies regarding glutathione that low glutathione, low cysteine, and high glutamate were a common problem in people with HIV. Those studies provide good guidelines on supplementing cysteine (NAC), but I haven't seen any details on the mechanism by which the virus drains glutathione.

What about those of us who have never had EBV or CMV? (As in multiple negative antibody and PCR tests)

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How about HHV-6? It's another herpesvirus. 99+% of the world's population has it by the time they're adults. Valcyte is used to treat CMV and HHV-6 and there has been some success with it in treating ME.

How about HHV-6? It's another herpesvirus. 99+% of the world's population has it by the time they're adults. Valcyte is used to treat CMV and HHV-6 and there has been some success with it in treating ME.

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Indeed. I should have mentioned that too. Although in my case i think teh cause was likely EBV, the cause for others could be one of the other herpes viruses. Or indeed a combination.

Thanks very much for offering a theory about how GcMAF could fit within your GD-MCB theory. It does make sense. Nonetheless, Id like to give you some data about my evolution, that maybe could give us a more detailed view on what is going on when a patient gets so better on GcMAF. Id really like to read your feedback, if you think the following items are worth giving an explanation or just commenting on:

1- Although I have improved clearly and significantly at the symptomatological level, the Th1/Th2 ratio (assessed by the ratio of 2 different pairs of cytokines) was still low. Interestingly my C4a had increased from a normal to a high value. (Note that these measurements were taken before my improvement was as good as it is now, so maybe things are different at this moment). My doctor thinks this rise in inflammation is a very good signal of my immune system working.

2- My doctor has told me that this is a usual pattern, i.e., symptoms wear off before tests results show it (I thought it was going to be the other way around).

3- My Nagalase was still high. Unfortunately I have not a previous measurement of it. If it has lowered, it means GcMAF is successfully killing whatever infections is giving off Nagalase.

4- Interestingly, my doctor told me that we could not expect a significant improvement until around 1 year of treatment, b/c this is the time lymphocytes need to fully replicate. Note that I have been 10 months on GcMAF, and the turning point in my improvement took place on the sixth month.

5- As you know, my main problem treatment-wise was that I could not tolerate any detoxtificator treatment, including the methylation supps. I tried B12 shots, chlorella, and lyposomal GSH as part of my regime, and I could not tolerate them the first time. Then, after a few months on the treatment, I decided to do a push treatment, in other words, to take these supps and shots, and just bear with the side-effects as I could, until my body detoxified enough in order to break this vicious cycle, hoping to be able to tolerate these protocol afterwards. This is indeed what happened. I can now tolerate this part of the treatment. (Although I am still incapable of tolerating the activated folates).

6- You know how much LDN helped me as a solo treatment. Actually it was my mainstay. Well, I have lowered it from 4.5 down to 2.5 mg, and I plan to stop it all slowly, and it seems that LDN is not my mainstay anymore. Maybe now my immune system is more free to fight infections.

And this is it! Maybe this info is interesting to you and others. I wish I could have had enough resources to measure GSH/GSSH during this process, but I havent been able to. However, I plan to do it in a few months, so I can compare with my previous one, when I was so so so so sick

Ill let you all know about my progress in the future, hoping it continues being so positive.

Thanks again for everything youre doing for us! I'll be always grateful to you!
Best wishes!
Sergio

I would also like to urge those people framing this drug as some kind of miracle cure to administer themselves a strong dose of scientific scepticism and cautiousness, the worst thing that could happen is a repeat of the XMRV drama. At the moment these results tell us nothing concrete about the underlying pathology, absolutely nothing - they took very detailed measurements of immune parameters and yet no trend emerged, that should be a strong warning sign that we are barely scratching the surface.

If I'm not mistaken Rich,you mention viral infection as one of the possible stressors that starts the vicious cycle. Is it not possible a virus that is able to get into our cells for some reason starts the process ? I mentioned a book I received from the library on glutatione. They showed that the 3 viruses they studied (HSV, influenza and HIV) all caused profound decreases in cellular glutathione.

In my case, I have enterovirus and it does make sense as I grew up spending a lot of time at a cottage using well water and my aunt has the same symptoms. I was not breastfed which would have negatively affected my immune system. Maybe a big enough dose of the virus would have circumvented the ability of my immune system to contain it and let it infect my cells and then reduce glutathione.

Regards, GP

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Hi, globalpilot.

I think that is very possible. In my view, viral infections can be either a cause or an effect (or both) of the vicious circle mechanism involving glutathione depletion, B12 functional deficiency, a partial block of the methylation cycle, and folate draining from the cells. It's true that at least some viruses (and also some bacteria) seem to have ways of lowering glutathione.

I hope this is the key to your case, and that you will be able to knock out the enteroviruses.